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The apoptotic efficacy of succinic acid on renal cancer cell lines

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Abstract

Recently, studies on the effects of non-toxic substances on cancer prophylaxis have gained value as an alternative to existing treatment options. Current studies have shown that succinic acid or its derivatives exhibit anticancer activity by inducing apoptosis. We aimed to investigate the anticancer activity of succinic acid on renal cancer for the first time in the literature. The cytotoxic activity of succinic acid on CAKI-2 and ACHN as renal cancer cell lines and MRC-5 as a healthy cell line was determined using the WST-1 cytotoxicity test. Apoptotic activity was measured by Annexin V test and cell death ELISA kit. The results showed that 25 μM and 50 μM doses of succinic acid for 24 h remarkably reduced the cell viability for CAKI-2 cells (89.77% and 90.77%) and ACHN cells (41.57% and 54.54%). Also, no significant effect was observed on the healthy cell line, as we expected. Additionally, administration of succinic acid at same doses resulted in apoptotic activity for ACHN cells (19.1 and 12.7) and CAKI-2 cells (19.85 and 29.55). ELISA results with same doses of succinic acid treatment increased the apoptotic fragment rates by 4.7 and 2.13-fold in CAKI-2 cells, and 32.92, 12.7-fold in ACHN cells. Succinic acid is a focal point for cancer treatments not only for its apoptotic success on cancer cells but also for its capacity to be metabolically active for humans. Our results suggest that succinic acid could be a potential therapeutic agent for individual cancer treatment approaches together with further molecular research.

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The data presented in this study are available on request from the corresponding author.

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References

  1. Cairns P. Renal cell carcinoma. Cancer Biomark. 2011;9(1–6):461–73. https://doi.org/10.3233/CBM-2011-0176.

    Article  CAS  PubMed Central  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

    Article  PubMed  Google Scholar 

  3. Rossi SH, Klatte T, Usher-Smith J, Stewart GD. Epidemiology and screening for renal cancer. World J Urol. 2018;36(9):1341–53. https://doi.org/10.1007/s00345-018-2286-7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs—part A: renal, penile, and testicular tumours. Eur Urol. 2016;70(1):93–105. https://doi.org/10.1016/j.eururo.2016.02.029.

    Article  PubMed  Google Scholar 

  5. Inamura K. Renal cell tumors: understanding their molecular pathological epidemiology and the 2016 WHO classification. Int J Mol Sci. 2017;18(10):2195. https://doi.org/10.3390/ijms18102195.

    Article  CAS  PubMed Central  Google Scholar 

  6. Kumar A, Kumari N, Gupta V, Prasad R. Renal cell carcinoma: molecular aspects. Indian J Clin Biochem. 2017;33(3):246–54. https://doi.org/10.1007/s12291-017-0713-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bonert M, El-Shinnawy I. Subtypes of renal cell carcinoma with defined genomic alterations: diagnostic and prognostic significance. Diagn Histopathol. 2018;24(6):191–7. https://doi.org/10.1016/j.mpdhp.2018.05.001.

    Article  Google Scholar 

  8. Dunnick NR. Renal cell carcinoma: staging and surveillance. Abdom Radiol. 2016;41(6):1079–85. https://doi.org/10.1007/s00261-016-0692-0.

    Article  Google Scholar 

  9. Cheng K-K, Zhao X-B, Zeng J, Zhang JA. Biotechnological production of succinic acid: current state and perspectives. Biofuels Bioprod Biorefin. 2012;6(3):302–18. https://doi.org/10.1002/bbb.1327.

    Article  CAS  Google Scholar 

  10. Zeikus JG, Jain MK, Elankovan P. Biotechnology of succinic acid production and markets for derived industrial products. Appl Microbiol Biotechnol. 1999;51:545–52. https://doi.org/10.1007/s002530051431.

    Article  CAS  Google Scholar 

  11. He W, Miao FJP, Lin DCH, Schwandner RT, Wang Z, Gao J, Chen JL, Tlan H, Ling L. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429(6988):188–93. https://doi.org/10.1038/nature02488.

    Article  CAS  PubMed  Google Scholar 

  12. Aguiar CJ, Rocha-Franco JA, Sousa PA, Santos AK, Ladeira M, Rocha-Resende C, Ladeira LO, Resende RR, Botoni FA, Melo MB, et al. Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation. Cell Commun Signal. 2014;12(1):1–17. https://doi.org/10.1186/s12964-014-0078-2.

    Article  Google Scholar 

  13. Robben JH, Fenton RA, Vargas SL, Schweer H, Peti-Peterdi J, Deen PMT, Milligan G. Localization of the succinate receptor in the distal nephron and its signaling in polarized MDCK cells. Kidney Int. 2009;76(12):1258–67. https://doi.org/10.1038/ki.2009.360.

    Article  CAS  PubMed  Google Scholar 

  14. Sadagopan N, Li W, Roberds SL, Major T, Preston GM, Yu Y, Tones MA. Circulating succinate is elevated in rodent models of hypertension and metabolic disease. Am J Hypertens. 2007;20(11):1209–15. https://doi.org/10.1016/j.amjhyper.2007.05.010.

    Article  CAS  PubMed  Google Scholar 

  15. Aguiar CJ, Andrade VL, Gomes ERM, Alves MNM, Ladeira MS, Pinheiro ACN, Gomes DA, Almeida AP, Goes AM, Resende RR, et al. Succinate modulates Ca2+ transient and cardiomyocyte viability through PKA-dependent pathway. Cell Calcium. 2010;47(1):37–46. https://doi.org/10.1016/j.ceca.2009.11.003.

    Article  CAS  PubMed  Google Scholar 

  16. Li X, Xie L, Qu X, Zhao B, Fu W, Wu B, Wu J. GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses. FASEB J. 2020;34(10):13091–105. https://doi.org/10.1096/fj.202001037R.

    Article  CAS  PubMed  Google Scholar 

  17. Iplik ES, Catmakas T, Cakmakoglu B. A new target for the treatment of endometrium cancer by succinic acid. Cell Mol Biol (Noisy-le-grand). 2018;64:60–3. https://doi.org/10.14715/cmb/2018.64.1.11.

    Article  Google Scholar 

  18. Ertugrul B, Iplik ES, Cakmakoglu B. In vitro inhibitory effect of succinic acid on T-cell acute lymphoblastic leukemia cell lines. Arch Med Res. 2020;20(1):31172–3. https://doi.org/10.1016/j.arcmed.2020.10.022.

    Article  CAS  Google Scholar 

  19. Wei CW, Yu YL, Chen YH, Hung YT, Yiang GT. Anticancer effects of methotrexate in combination with α-tocopherol and α-tocopherol succinate on triple-negative breast cancer. Oncol Rep. 2019;41:2060–6. https://doi.org/10.3892/or.2019.6958.

    Article  CAS  PubMed  Google Scholar 

  20. Yu W, Sanders BG, Kline K. RRR-α-tocopheryl succinate-induced apoptosis of human breast cancer cells involves bax translocation to mitochondrial. Cancer Res. 2003;63(10):2483–91.

    CAS  PubMed  Google Scholar 

  21. Nakamura N, Hirakawa A, Gao JJ, Kakuda H, Shiro M, et al. Five new maleic and succinic acid derivatives from the mycelium of Antrodia camphorata and their cytotoxic effects on LLC tumor cell line. J Nat Prod. 2004;67(1):46–8. https://doi.org/10.1021/np030293k.

    Article  CAS  PubMed  Google Scholar 

  22. Sánchez-Rodríguez C, Palao-Suay R, Rodrigáñez L, et al. α-Tocopheryl succinate-based polymeric nanoparticles for the treatment of head and neck squamous cell carcinoma. Biomolecules. 2018;8(3):97. https://doi.org/10.3390/biom8030097.

    Article  CAS  PubMed Central  Google Scholar 

  23. Hossain SM, Chowdhury EH. Citrate- and succinate-modified carbonate apatite nanoparticles with loaded doxorubicin exhibit potent anticancer activity against breast cancer cells. Pharmaceutics. 2018;10(1):32. https://doi.org/10.3390/pharmaceutics10010032.

    Article  CAS  Google Scholar 

  24. Lim SJ, Choi MK, Kim MJ, Kim JK. α-Tocopheryl succinate potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in human H460 lung cancer cells. Exp Mol Med. 2009;41(10):737–45. https://doi.org/10.3858/emm.2009.41.10.080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Emami J, Rezazadeh M, Rostami M, et al. Co-delivery of paclitaxel and α-tocopherol succinate by novel chitosan-based polymeric micelles for improving micellar stability and efficacious combination therapy. Drug Dev Ind Pharm. 2015;41(7):1137–47. https://doi.org/10.3109/03639045.2014.935390.

    Article  CAS  PubMed  Google Scholar 

  26. Hahn T, Szabo L, Gold M, et al. Dietary administration of the proapoptotic vitamin E analogue α-tocopheryloxyacetic acid inhibits metastatic murine breast cancer. Cancer Res. 2006;66(19):9374–8. https://doi.org/10.1158/0008-5472.CAN-06-2403.

    Article  CAS  PubMed  Google Scholar 

  27. Neuzil J, Weber T, Gellert N, et al. Selective cancer cell killing by α-tocopheryl succinate. Br J Cancer. 2001;84:87–9. https://doi.org/10.1054/bjoc.2000.1559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Patacsil D, Osayi S, Tran AT, et al. Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells. Genes Nutr. 2012;7(1):83–9. https://doi.org/10.1007/s12263-011-0242-x.

    Article  CAS  PubMed  Google Scholar 

  29. Alqahtani S, Kaddoumi A. Vitamin E transporters in cancer therapy. AAPS J. 2015;17(2):313–22. https://doi.org/10.1208/s12248-014-9705-5.

    Article  CAS  PubMed  Google Scholar 

  30. Neuzil J. Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity. Br J Cancer. 2003;89(10):1822–6. https://doi.org/10.1038/sj.bjc.6601360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Weber T, Lu M, Andela L, et al. Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factorrelated apoptosis-inducing ligand (Apo2 ligand) in vivo. Clin Cancer Res. 2002;8(3):863–9.

    CAS  PubMed  Google Scholar 

  32. Zhang X, Peng X, Yu W, et al. Alpha-tocopheryl succinate enhances doxorubicin-induced apoptosis in human gastric cancer cells via promotion of doxorubicin influx and suppression of doxorubicin efflux. Cancer Lett. 2011;307(2):174–81. https://doi.org/10.1016/j.canlet.2011.04.001.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by Istanbul University Scientific Research Committee (Grant number: 32550).

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Authors and Affiliations

  1. Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Capa, Istanbul, Turkey

    Goksu Kasarci, Baris Ertugrul & Bedia Cakmakoglu

  2. Department of Medical Biochemistry, Faculty of Medicine, Istanbul Health and Technology University, Istanbul, Turkey

    Elif Sinem Iplik

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  1. Goksu Kasarci
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  2. Baris Ertugrul
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  3. Elif Sinem Iplik
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  4. Bedia Cakmakoglu
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Contributions

Conceptualization, GK, BE, ESI and BC; methodology, GK, BE and ESI; validation, GK and BE; formal analyses, ESI and BC; investigation, GK, BE and ESI; supervision, BC; project administration, BC. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Bedia Cakmakoglu.

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Kasarci, G., Ertugrul, B., Iplik, E.S. et al. The apoptotic efficacy of succinic acid on renal cancer cell lines. Med Oncol 38, 144 (2021). https://doi.org/10.1007/s12032-021-01577-9

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